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New Brain ‘Channel’ Key to Preventing Opioid-Induced Respiratory Depression

February 3, 2016
Respiratory depression is a major risk facing patients taking high doses of opioid drugs. New research is revealing how opioids affect breathing, something that could help develop future life-saving therapies.

Interview with Gaspard Montandon, PhD

Over 15,000 Americans die every year from respiratory depression-related overdoses while taking a prescription opioid.1,2 There may be a way to prevent respiratory depression, without nullifying the pain-relieving benefits patients need from these analgesics, according to new research published in Anesthesiology.3

The key lies in understanding how opioids and μ-opioid receptors (MOR) mediate respiratory depression in the human brain, and a group of researchers now believe they may have located the very spot where opioid-induced respiratory depression is primarily triggered.

The spot is located in the pre-Bötzinger complex (preBötC), a small cluster of highly opioid-sensitive interneurons found in the medulla. These neurons are significant to the generation of breathing rhythm in mammals,4,5 but up to this point, doctors did not understand how MOR could affect the brainstem respiratory network—until now.

The New Study

In the new study, researchers administered a centrally acting non-opioid analgesic to the preBötC to see how it caused respiratory depression in typical wild-type mice. The analgesic, called flupirtine, is known to be a prime opener of G-protein-gated inwardly rectifying potassium (GIRK) channels,6 which help shape the behavior of neural circuits in the body.

The investigators confirmed that flupirtine (300 μM) did reduce the mice’s respiratory rates by 22.2%.6 However, they believe that a specific sub-unit, GIRK2, is a significant driver of much of this drug-induced respiratory depression. The absence of GIRK2 has been found to mute many of the functional GIRK channels found in the brain,7 so when flupirtine was administered to the preBötC of mice lacking the GIRK2 subunit (GIRK2−/−), there was no effect on the respiratory rate.

The next step was to compare the effects of two MOR-agonist, the synthetic opioid peptide [d-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and fentanyl. A recurring pattern emerged. At baseline, wild-type and GIRK2 mice had similar respiratory rates, but when administered 5 μM of DAMGO, significantly depressed respiratory rate in wild-type mice compared with GIRK2 mice. Respiratory rate depression by systemic injection of fentanyl was markedly reduced in GIRK2 mice compared with wild-type mice.

According to the lead author of the study Gaspard Montandon, PhD, from the University of Toronto, these findings could influence how researchers approach the prospect of developing therapies to prevent opioid-induced respiratory depression.

"There are several ways that opioids can cause breathing problems, but this is a crucial one [GIRK channels]," said Dr. Montandon in an interview with Practical Pain Management. “Our study is the first to clearly identify a type of potassium channels [GIRK2] contributing to respiratory rate depression by opioid drugs. This is the first time anyone has identified where and how opioids work—and how to shut down their most dangerous effects."

"This is a very exciting field of research because our current armamentarium of pure opioid agonists come with significant risks for opioid-induced respiratory depression (OIRD),” said Jeffrey Fudin, PharmD, Clinical Pharmacy Specialist in Pain Management and Director, PGY2 Pain & Palliative Care Pharmacy Pain Residency at Samuel Stratton VA Medical Center, in Albany, NY.

Caveats to Consider

By using highly specific MOR agonists, Dr. Montandon and his colleagues are confident they have found a significant pathway showing how GIRK channels affect the respiratory depression typically found in overdose patients.8,9 There could be important caveats to consider, however, like the fact the flupirtine dose probably diffused beyond the preBötC brain region.

Also, fentanyl does have a broad action on the central nervous system (CNS) and periphery neurons. While no fentanyl-induced respiratory arrest was found in GIRK2−/− mice, there was still a moderate decrease in breathing rates, likely because fentanyl affected some other component of the respiratory network, like the adenylyl cyclase pathway10 or the presynaptic inhibition of voltage-dependent calcium channels,11 the investigators noted.

“Morphine or oxycodone could also be tested, but these two drugs also target µ-opioid receptors, so it is likely that we might obtain similar results,” said Dr. Montandon. However, this still could be cause for further inquiry, as some agents in the pain management armamentarium do present distressing characteristics, such as remifentanil.

Limitations of Current Solutions

Remifentanil (Ultiva) is a MOR-agonist used during surgery, which has a similar potency to fentanyl but with a rapidly diminishing effect on respiratory hypoxic drive, which can happen within minutes after administration.12 Naloxone, the typical choice for reversing respiratory depression, does not show a discernible effect on remifentanil, which could force doctors to stop the remifentanil infusion during surgery, thus compromising analgesia.1

Buprenorphine also shows serious resistance to naloxone-reversal, even at high doses up to 10 mg.13 Some opioid agonists simply have a longer plasma half-life than naloxone, which presents the risk of renarcotization, especially in an emergency situation where bolus doses of naloxone may have been used. Quick agents like alfentanil could present these scenarios and require target-controlled infusion regimens to keep both analgesia and adequate breathing in check.14

Naloxone itself presents its own cardiopulmonary risks, especially when used in high doses or rapid administration. Naloxone can induce a release of catecholamines, leading to catecholamine-mediated cardiac arrhythmias and vasoconstriction, not to mention cardiac arrest, pulmonary edema, and epileptic seizures.15,16

Preventing Respiratory Depression, Preserving Pain Management

“There are currently no pharmacological strategies at preventing respiratory depression without altering opioid analgesia,” said Dr. Montandon.

The development of new, more-sophisticated therapies to treat respiratory depression is a major area of research. The detection of the GIRK2 sub-unit as a major component of opioid respiratory depression could be a serious breakthrough.

The challenge behind pharmacologically blockading GIRK channels is that they’re so widely distributed in the body, including the heart and endocrine systems.17

“Although there are currently no drugs to specifically target GIRK channels, there is a growing interest in developing new drugs that target GIRK channels with specific subunits. Such drugs would be able to prevent respiratory depression without reducing analgesia by opioid drugs,” said Dr. Montandon.

This may very well be achieved through selectively targeting specific sub-unit compositions like GIRK2, developing subunit-selective GIRK modulators, or perhaps targeting components of the GIRK channel pathway—all burgeoning areas of research that may someday yield significant, life-saving interventions.18,19

“Strategically targeting or avoiding certain GIRK channels to mitigate against OIRD in at-risk patients would be a huge therapeutic breakthrough for acute and chronic patients requiring opioid therapy,” Dr. Fudin told Practical Pain Management. “The greatest challenge in my mind would be targeting specific GIRK channels within the CNS without affecting GIRK channels in the periphery."

This study was supported by the Parker B. Francis Fellowship, Tier 1 Canada Research Chair, the National Sanitarium Association Innovative Research Program, the National Institutes for Health, the National Institute on Drug Abuse Training, and the Canadian Institutes for Health Research. The authors declared no conflicts of interest.

Last updated on: February 3, 2016
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HHS Releases Steps to Stem Opioid-related Overdose, Death and Dependence

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